Good morning, myeloma world.

After a particularly busy inaugural edition of Myeloma Morning ^[1], today's edition doesn't have quite as much ground to cover. We'll be focusing most of today's discussion on just four new research studies that have been published.

That being said, the first of those studies is going to require more than the usual amount of attention.

That's because the study is a new International Myeloma Working Group (IMWG) consensus state­ment concerning high-risk cytogenetics – a subject of significant interest to almost everyone in myeloma world (abstract ^[2]).

(Recall that “cytogenetics” is short hand for “chromosomal abnormalities a myeloma patient has in their myeloma cells.” Having “high-risk cytogenetics” means that a patient has chromosomal abnormalities associ­ated with more aggressive, more difficult-to-treat, multiple myeloma.)

Before saying much more, it should be emphasized that the IMWG consensus statement is really about high-risk cytogenetics in newly diagnosed multiple myeloma patients. While high-risk chromosomal abnormalities often are discussed in connection with relapsed myeloma, most of the work that has been done by myeloma specialists on the topic has been with newly diagnosed patients. So that is the focus of the IMWG consensus statement.

The key initial item of interest in the consensus statement is the IMWG definition of high-risk cyto­genetics. The article states that t(4;14), t(14;16), t(14;20), and del(17/17p) are to be considered high-risk chromosomal abnormalities.

In addition, having a non-hyperdiploid karyotype is also to be considered a sign of high-risk disease. A “non-hyperdiploid karyotype” occurs when a patient's myeloma cells have less than 48, or more than 74, chromo­somes.

Finally, the working group states that “Gain(1q) is associated with del(1p) carrying poor risk”, and that having 3 or more chromo­somal abnormalities is a marker of “ultra-high-risk” disease.

The consensus statement turns next to IMWG recommendations on how newly diagnosed patients with high-risk cytogenetics should be treated. Most of the focus during this discussion is on the treatment of high-risk newly diagnosed patients with either the t(4;14) or del(17p) chromosomal abnormalities.

The IMWG recommends that these patients be treated with a proteasome inhibitor, such as Velcade (bor­tezo­mib) or Kyprolis (car­filzomib), in combination with dexamethasone and either Revlimid (lena­lido­mide) or Pomalyst (pomalidomide). The authors somewhat favor Velcade over Kyprolis – but just somewhat.

The working group also comes out strongly in favor of autologous stem cell transplantation for any newly diagnosed myeloma patient who is transplant eligible and has high-risk cytogenetics. In fact, the working group recommends tandem autologous stem cell transplants – two autologous transplants, one after the other – for these patients.

As for allogeneic (donor) stem cell transplants for high-risk patients, the working group says the following:

Allogeneic SCT or tandem auto-allo-SCT may improve PFS in patients with t(4;14) or del(17p). Results are better in an early stage of the disease. The novel treatments may challenge the role of allo-SCT and its use should be restricted to clinical trials.

There are three other new research papers we'd like to discuss quickly in today's Myeloma Morning.

First, French researchers have published results of a clinical trial comparing treatment of newly diagnosed, transplant-eligible multiple myeloma patients with either Velcade, thalidomide, and dexamethasone (VTD), or Velcade, cyclophosphamide (Cytoxan), or dexamethasone (VCD / CyBorD) (abstract ^[3]).

Patients in the trial who were treated with VTD were more likely to achieve a very good partial response or better, compared to the patients treated with VCD (66 percent of the VTD patients versus 56 percent of the VCD patients). There was no significant between the groups in how often patients experienced serious side effects. There was, however, a difference in the type of serious side effects the patients experienced, with VTD being more likely to cause peripheral neuropathy, while VCD was more likely to cause low blood cell counts.

The researchers believe their findings further strengthen the case for combining an immunomodulatory agent, such as thalidomide or Revlimid, with a proteasome inhibitor, such as Velcade, and with dexamethasone when treating newly diagnosed myeloma patients.

Second, a team of U.S. researchers has reported results of a Phase 1 trial investigating marizomib (NPI-0052, salinosporamide A) as a potential new treatment for multiple myeloma. Marizomib is in the same class of drugs, known as proteasome inhibitors, as Velcade, Kyprolis, and Ninlaro (ixazomib).

The marizomib trial was conducted in a total of 68 relapsed multiple myeloma patients. Its objective was to determine the recommended dose for a Phase 2 trial of marizomib, which would focus more on testing the efficacy of the drug as a treatment for multiple myeloma. Given the objective of the Phase 1 trial, numerous dose levels – and two different dose schedules – were tested during the study. In addition, the formulation of marizomib also was modified during the trial

The patients in the trial were heavily pretreated, having an average of more than five prior treatments. Thus, not many of the patients responded to the marizomib – 6 of the 68 patients had a minimal response or better (1 minimal response, 5 partial responses). Nevertheless, the researchers believe the drug should go on for further evaluation in the planned Phase 2, saying the drug's tolerability and potential efficacy justify additional investigation of its potential.

The final new research article we'll look at today is from a team of U.S. researchers. They developed a mathematical model describing multiple myeloma cells and how they react to treatment (abstract ^[4]). The model was developed using a database of treatment responses from three trials that investigated Velcade in multiple myeloma patients.

Based on their initial work on the model and further refinement, the authors came up with a “hybrid” model. It describes multiple myeloma as consisting of two types of cells – "progenitor cells" and "differentiated cells." The latter type of cells are considered to be be more responsive to treatment, and the mix and type of cells present evolves over time in response to treatment.

We don't have any business-related myeloma news to report today. We do have, however, several discussions from the Beacon's forum that we want to highlight, including one about high fevers after Zometa infusions ^[5], another about a study looking at interferon for multiple myeloma ^[6] (!), the latest update from Debbie ^[7] during her autologous stem cell transplant, and almost 30 different discussions about Darzalex (daratumumab) ^[8].

New myeloma-related research articles

1. Moreau, P. et al., “VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial” in Blood, March 21, 2016 (abstract ^[3])
2. Richardson, P. et al., “Phase 1 study of marizomib in relapsed or relapsed and refractory multiple myeloma; NPI 0052 101 Part 1” in Blood, March 23, 2016 (abstract ^[4])
3. Sonneveld, P. et al., “Treatment of Multiple Myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group” in Blood, March 21, 2016 (abstract ^[2])
4. Tang, M. et al., “Myeloma cell dynamics in response to treatment supports a model of hierarchical differentiation and clonal evolution” in Clinical Cancer Research, March 6, 2016 (abstract ^[9])